Two-Step Crystallization Process Strategy for Cannabidiol Isolation at Higher Yields

Abstract We describe a Two-step DMA-MediAted Crystallization method (2DMAC-method) for the first time. This two-step strategy for the purification of cannabidiol (CBD) utilizes N,N-dimethylacetamide (DMA) to form an isolable CBD·2DMA solid solvate, which precipitates from cooled heptane. The 2DMAC-method is selective for CBD, as the solvate is free of tetrahydrocannabinol (THC). DMA can subsequently be removed via aqueous washing, and the free CBD is crystallized from heptane. Overall, the 2DMAC-method delivers higher recovery and tighter impurity control compared to a standard industry method. Across three samples, final CBD recoveries averaged 61% with the 2DMAC-method, versus 48% for a standard heptane crystallization. All CBD isolates obtained via the solvate reached ≥97.5% CBD, with nondetectable THC by HPLC, LC-MS, and NMR, in line with common method purities. Additionally, the 2DMAC-method was more effective in removing cannabidivarin (CBDV) and the toxic, oxidative impurity HU-331 (CBD hydroxyquinone).